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. 2026 Apr 10;19:87. doi: 10.1186/s12920-026-02355-0

Association between the IGFBP-3 rs2854744 polymorphism and cancer risk: a meta-analysis

Dan Sun 1,#, Lihua Xu 1,#, Yajuan Chen 1, WanJu Wang 1, Na Wang 1,✉,#, Gang Hu 1,✉,#
PMCID: PMC13192136  PMID: 41963924

Abstract

Background

Recently, the association of IGFBP-3 polymorphism and cancer risk has attracted many attentions. Previous studies have shown that IGFBP-3 rs2854744 was associated with cancer, but the results were conflicting.

Method and results

We performed a meta-analysis including 33 studies with 24,688 cases and 28,972 controls to seek the association among them. A significant increase of cancer risk was found between the IGFBP-3 rs2854744 Polymorphism and cancer risk in Recessive Model (CC vs. AC/AA: OR = 1.097, 95%CI: 1.020, 1.180, P < 0.05). While in subgroup analysis, A same increase of breast cancer risk also have been shown in our study in Recessive Model (CC vs. AC/AA: OR = 1.126, 95%CI: 1.007, 1.260, P < 0.05).

Conclusions

The results of our meta-analysis concluded that the IGFBP-3 rs2854744 polymorphism was closely related with the increase of cancer risk while further large size case–control studies are required.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12920-026-02355-0.

Keywords: IGFBP-3, Polymorphism, Cancer

Introduction

As an evolutionarily conserved axis believed to regulate carbohydrate metabolism, the growth hormone-insulin-like growth factor (GH-IGF) axis is recognized for its role in maintaining the physiological function and metabolism of various tissues [1, 2]. The insulin-like growth factors (IGFs) are crucial in modulating cell proliferation and apoptosis [3, 4]. Numerous in vitro studies have demonstrated that IGFs act as potent catalysts for the proliferation of various cancer cell types while also exerting an inhibitory effect on cell apoptosis. This dual role significantly contributes to tumor cell growth [5, 6]. The interaction between IGFs and their receptors is modulated by insulin-like growth factor binding proteins (IGFBPs). Among these, IGFBP-3 is particularly significant, as it regulates over 90% of circulating IGFs in the serum [7]. These findings provide a basis for hypothesizing a link between IGFBP-3 and cancer risk. Recent research has shown that the IGFBP-3 rs2854744 polymorphism is significantly associated with reduced levels of IGFBP-3 in blood, as evidenced by both in vitro and in vivo studies [8, 9]. The studies conducted have yielded varying and sometimes conflicting results regarding the association between IGFBP-3 rs2854744 polymorphism and cancer risk. Mehta's study suggested that low IGFBP-3 levels are associated with an increased risk of prostate cancer. In contrast, Morris and colleagues found no significant association between IGFBP-3 levels and prostate cancer risk [10, 11]. Nomura's research indicated that decreased IGFBP-3 levels are linked to a higher incidence of colorectal cancer, a finding that Teramukai's study corroborated [12, 13]. To further investigate the relationship between IGFBP-3 rs2854744 polymorphism and cancer risk, we conducted a meta-analysis to examine the association of this gene polymorphism with overall cancer risk and its impact on various cancer types. Previous studies have demonstrated that IGFs play a role in mediating cell proliferation across several tissues, including lung, prostate, breast, and colorectal epithelial cells [14]. Therefore, we categorized the malignant tumor types in our analysis as lung cancer, colorectal cancer, breast cancer, prostate cancer, and other cancers.

Method

Identification of eligible studies

A literature search was preformed basing on the PubMed database, Web of Science, Chinese Wan Fang databases and Chinese National Knowledge Infrastructure (CNKI) with the key words: “IGFBP3” and (“polymorphism” or “single nucleotide polymorphism” or “SNP” or “variation”)and(“cancer”or “carcinoma” or “ tumor”) until August 1,2023. Searching was performed without limitation on language or publication years. Clinical trial number: not applicable.

Exclusion and inclusion criteria

Studies were picked out if they met the following conditions: (1)case and control studies; (2) focusing on the association between IGFBP3 rs2854744 SNP and cancer risks; (3) providing detail genotype frequencies. Those studies with no detail genotype frequencies were excluded.

Data extraction

We extracted data for all eligible studies according to different cancer types and different genotypes, and collected the first author of these studies, the year of publication, the type of cancer, the numbers of cases and controls, and the frequency of each genetype in the cases and controls.

Statistical analysis

Chi-square tests were employed to assess Hardy–Weinberg equilibrium in the gene frequencies of the control groups across all included studies. To analyze the association between the IGFBP3 rs2854744 single nucleotide polymorphism (SNP) and cancer risk, we utilized five genetic models: the allele model (A vs. C), the heterozygote model (AC vs. AA), the homozygote model (CC vs. AA), the dominant model (AC/CC vs. AA), and the recessive model (CC vs. AC/AA). The strength of the association was quantified using the Odds Ratio (OR) with 95% Confidence Intervals (95% CI). The Q statistic test, based on the chi-square distribution, was conducted to evaluate between-study heterogeneity. A p-value of less than 0.10 or an I2 statistic greater than 50% was considered indicative of significant heterogeneity [15]. In the presence of heterogeneity, a random-effects model was applied to calculate the pooled OR for each study. Publication bias was assessed using Begg’s funnel plot. All statistical analyses were performed using Stata software, version 11.0.

Results

Characteristics of eligible studies

There were 7431 potentially eligible studies were searched by the initial screening. According to inclusion and exclusion criteria, 14 articles were excluded for the reason of no detailed genotyping information, 5259 articles were not focus on cancer and 2125 articles were not related to rs2854744. The specific process was shown in Fig. 1. After all, there were 33 eligible studies, including 24,688 cases and 28,972 controls, relevant to the association between IGFBP-3 rs2854744 polymorphism and cancer risk. In the 33 eligible studies, 7 of them were studies of Breast Cancer (BC), 12 studies were of Prostate Cancer (PC), 6 studies were of Colorectal Cancer (CC), only 2 studies were of Lung Cancer (LC) and 6 studies were of Other Cancer (OC) (details shown in Table 1).

Fig. 1.

Fig. 1

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Study flow chart explaining the selection of the 33 eligible article

Table 1.

Characteristics of eligible studies

Author Year cancertype Case Control p-value(HWE)
AA AC CC AA AC CC
Wong et. al 2005 CC 166 90 16 480 306 35 0.112
Ren et. al 2004 BC 641 405 63 708 455 44 0.005
Cheng et. al 2006 PC 687 1002 590 720 954 581 8.426
Cheng et. al 2006 BC 502 673 389 598 891 431 4.520
Moon et. al 2006 LC 131 73 5 95 91 23 8.631
Wagner et. al 2005 BC 57 210 156 122 289 238 4.152
Hernandez et. al 2007 PC 112 197 92 113 183 70 7.889
Wang et. al 2003 PC 189 100 18 152 105 15 5.693
Schildkra et. al 2005 PC 18 55 27 23 41 28 3.090
Al-Zahrani et. al 2006 BC 834 2150 1327 940 2203 1306 8.457
Slattery et. al 2006 CC 497 1090 690 631 1465 838 8.440
Canzian et. al 2006 BC 200 368 208 369 743 407 4.106
Nam et. al 2003 PC 135 233 115 145 274 129 9.841
Chen et. al 2006 PC 55 91 67 47 103 63 6.895
Li et. al 2004 PC 97 217 126 139 225 115 2.029
Han et. al 2008 LC 236 152 22 247 141 23 6.274
Pechlivan et. al 2007 CC 135 314 165 122 262 163 3.915
Chen et. al 2008 OC 353 192 31 419 199 29 3.902
Elisabeth et. al 2010 CC 37 59 25 504 845 381 4.501
Chen et. al 2008 OC 353 192 31 419 199 29 1.567
Zhao et. al 2015 OC 26 51 33 45 55 28 4.391
Mohammad et. al 2011 OC 22 85 55 82 155 87 2.778
Touraj et. al 2014 CC 43 126 92 61 154 124 1.433
Christopher et. al 2009 OC 49 155 113 33 148 114 0.473
Zhang et al 2015 PC 1926 1059 147 1616 786 87 0.626
Qian et. al 2014 PC 408 225 31 424 246 32 0.588
Safarinejad et. al 2011 PC 23 85 60 89 163 84 0.741
Park et. al 2009 PC 128 76 21 140 76 9 0.762
H. Li et. al 2016 BC 85 46 9 96 55 9 0.428
Temitope et. al 2012 CC 83 111 46 106 153 66 0.174
Guiming et. al 2016 PC 48 447 922 22 292 694 0.444
Wang et. al 2013 OC 11 52 35 45 70 35 0.930
Xiaobin et. al 2015 BC 246 179 40 483 277 39 0.608
Gu Jun et. al 2014 OC 242 138 24 268 136 20 0.112
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Type of cancer: ‘CC’ for colonrectal cancer, ‘BC’ for breast cancer, ‘PC’ for prostate cancer; ‘LC’ for lung cancer and ‘OC’ for other cancer

Meta-analysis results

In the overall analysis, we found a significant association between IGFBP3 rs2854744 polymorphism and the risk of cancer in recessive model(CC vs. AC/AA: OR = 1.097, 95%CI: 1.020,1.180;P < 0.05 I2 < 50%), Same results were shown both in homozygote model(CC vs. AA: OR = 1.177,95%CI: 1.056,1.311; P < 0.05 I2 > 50%) and allele model (A vs. C: OR = 1.060, 95%CI: 1.008, 1.115; P < 0.05 I2 > 50%). However, the heterozygote model and dominant model had proved no obvious association between the IGFBP3 rs2854744 polymorphism and cancer risk.We used the random effects model to pool the result, all of these was shown in Fig. 2.

Fig. 2.

Fig. 2

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Forest plots of IGFBP3 rs2854744 polymorphism and cancer for all eligible studies. a recessive model: CC vs. AC/AA. b dominant model: AC/CC vs. AA. c allele model: A vs. C. d homozygote model: CC vs. AA

The sub-group analyses were performed to evaluate the influence of cancer types. An increased risk of breast cancer was fund in recessive model (CC vs. AC/AA: OR = 1.126, 95%CI: 1.007, 1.260; P < 0.05), homozygote model (CC vs. AA: OR = 1.204, 95%CI: 1.035, 1.401; P < 0.05) and allele model (A vs. C: OR = 1.071, 95%CI: 1.008, 1.137; P < 0.05). No association was fund both in prostate cancer and colorectal cancer between the IGFBP-3 rs2854744 Polymorphism and them. While in Lung cancer, all five models have shown a tendency of decrease risk between the IGFBP-3 rs2854744 Polymorphism and it, however, the research of this topic seems to be so pool.

Heterogeneity

No significant heterogeneity was fund in colorectal cancer, breast cancer and prostate cancer but for lung cancer and other cancer.

Publication bias

We used the Begg’s funnel plot test to evaluate the publication bias. Since no obvious asymmetry was fund in all five genetic models, it is reasonable to believe that there was no significant publication bias among our study. The detailed result was shown in Fig. 3.

Fig. 3.

Fig. 3

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Funnel plots for all publications a homozygote model b recessive model c heterozygote model. d allele model

Discussion

In our meta-analysis, we examined 33 studies encompassing 24,688 cancer cases and 28,972 healthy controls to assess the association between the IGFBP-3 rs2854744 single nucleotide polymorphism (SNP) and cancer risk. The IGFBP-3 rs2854744 polymorphism was associated with an increased risk of cancer, but this increased risk was not observed in all types of cancer. In subgroup analyses, the increased risk was significant only in breast cancer, but not in most other cancers. Even in lung cancer, the effect was inverse, although it is not convincing because of the small number of data.

Previous studies had shown that the IGFBP-3 rs2854744 polymorphism was not associated with the risk of colorectal cancer [16, 17], and our study confirmed this view with newer and more complete data on the basis of them. Although only breast cancer was found to be associated with IGFBP-3 rs2854744 polymorphism in subgroup analyses, positive associations were found in other categories of cancers (including esophageal cancer and bladder cancer) in both allele and dominant model subgroup analyses. It is just that there are too few studies related to this classification of cancers and IGFBP-3 rs2854744 polymorphism to definitively verify the association of individual diseases with IGFBP-3 rs2854744 polymorphism.

In our study, it seems that for most cancers, the IGFBP-3 rs2854744 polymorphism may increase the risk of disease or show a trend of increasing the risk of disease, but this trend was shown in the opposite direction in only two studies on lung cancer, although the data were not statistically significant. Study had shown that in the circulatory system, the majority of IGF-1 is bound to IGFBP-3. The IGFBP-3 protein can regulate IGF-1 activity through competitive inhibition [18]. IGFBP-3 inhibits the biological activity of IGF by blocking its binding to the receptor; conversely, it can enhance IGF action by preventing its degradation [19, 20]. On the other hand,the effect of IGFBP-3 on cancer cell growth is influenced by both time and concentration, varying according to the patient [21]. This complex physiological mechanism may partly explain the difference.

Among the 33 eligible studies [16, 17, 20, 22–48], Canzian and colleagues identified a significant association between the −202 A > C polymorphism and an increased risk of breast cancer in Caucasian populations. Similarly, Wagner's study demonstrated that the CC alleles of the IGFBP-3 rs2854744 polymorphism were significantly associated with an increased risk of breast cancer in Polish individuals [26]. Our study also confirmed this association between the IGFBP-3 A-202C polymorphism and breast cancer. In contrast, for prostate cancer, Wang's study found no differences in allele frequencies among patients, a finding corroborated by Nam [28, 33]. However, Hernandez's research indicated that individuals with the CC genotype at the rs2854744 locus of the IGFBP-3 gene had a significantly increased risk of prostate cancer [27]. Our results showed no significant association between the IGFBP-3 A-202C SNP and prostate cancer. Zhiqiang's meta-analysis reached a similar conclusion, although they initially excluded a study for questionable reasons. Subsequently, they identified that the IGFBP-3 rs2854744 SNP was indeed related to prostate cancer susceptibility [49]. No significant association was identified between the IGFBP-3 rs2854744 polymorphism and colorectal cancer risk across the six eligible studies examined.

Regarding limitations, due to the limited number of studies and the fact that many hospitals in the included studies enrolled patients with more mixed races and presented data that did not separate these, we were unable to perform subgroup analyses based on ethnicity. However, existing studies have shown that ethnic differences play A large role in the association between IGFBP-3 A-202C polymorphism and cancer. Additionally, factors such as environmental influences and lifestyle should also be considered. Moreover, most control groups in our study were hospital-based rather than population-based, which also warrants consideration. Finally, only studies published in English and Chinese were included in the analysis.

Our meta-analysis has demonstrated a significant association between the IGFBP-3 rs2854744 polymorphism and cancer risk, with a notable impact on breast cancer. To substantiate these findings, additional large-scale case–control studies are necessary. 

Supplementary Information

Supplementary Material 1. (267.3KB, docx)

Acknowledgements

Not applicable.

Authors’ contributions

Dan Sun performed the experiments and wrote the article. Lihua Xu and Gang Hu performed the experiments. Yajuan Chen revised the article.Na Wang and wanju Wang designed the study and reviewed the article. All authors read and approved the final manuscript as submitted.

Funding

Not applicable.

Data availability

Data is provided within the manuscript or supplementary information files.

Declarations

Ethics approval and consent to participate

Not Applicable.

Consent for publication

Not Applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Dan Sun, Lihua Xu, Na Wang and Gang Hu were contributed equally to this work.

Contributor Information

Na Wang, Email: wangna@zgwhfe.com.

Gang Hu, Email: 294697597@qq.com.

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Supplementary Materials

Supplementary Material 1. (267.3KB, docx)

Data Availability Statement

Data is provided within the manuscript or supplementary information files.

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